Synthesis and CYP24A1-Dependent Metabolism of 23-Fluorinated Vitamin D3 Analogues

Fumihiro Kawagoe; Kaori Yasuda; Sayuri Mototani; Toru Sugiyama; Motonari Uesugi; Toshiyuki Sakaki; Atsushi Kittaka

doi:10.1021/acsomega.9b01500

Synthesis and CYP24A1-Dependent Metabolism of 23-Fluorinated Vitamin D₃ Analogues

ACS Omega. 2019 Jun 28;4(6):11332-11337. doi: 10.1021/acsomega.9b01500. eCollection 2019 Jun 30.

Authors

Fumihiro Kawagoe^{1

2}, Kaori Yasuda³, Sayuri Mototani¹, Toru Sugiyama¹, Motonari Uesugi^{2

4}, Toshiyuki Sakaki³, Atsushi Kittaka^{1

2}

Affiliations

¹ Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
² AMED-CREST, The Japan Agency for Medical Research and Development (AMED), Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
³ Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
⁴ Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.

Abstract

Two novel 23-fluorinated 25-hydroxyvitamin D₃ analogues were synthesized using Inhoffen-Lythgoe diol as a precursor of the CD-ring, efficiently. Introduction of the C23 fluoro group was achieved by the deoxy-fluorination reaction using N,N-diethylaminosulfur trifluoride or 2-pyridinesulfonyl fluoride (PyFluor). Kinetic studies on the CYP24A1-dependent metabolism of these two analogues revealed that (23S)-23-fluoro-25-hydroxyvitamin D₃ was more resistant to CYP24A1-dependent metabolism than its 23R isomer.